Summary: A new study reveals a commonality in gene activity related to the same immune response and inflammatory pathways in the brains of patients with Parkinson’s and Huntington’s disease.

Source: BMC.

A new study strongly suggests that the brains of people who have died of Huntington’s disease (HD) and Parkinson’s disease (PD) show a similar response to a lifetime of neurodegeneration, despite being two very distinct diseases.

The findings, which appear in the journal Frontiers in Molecular Neuroscience, found that most of the genes perturbed in brains from both diseases are related to the same immune response and inflammatory pathways. Inflammation in the central nervous system has recently been shown to play a role in a number of different neurodegenerative diseases, including HD and PD, but this is the first direct comparison of these two distinct diseases.

Brains of individuals who died with Huntington’s, Parkinson’s or no neurological condition were analyzed using sequencing technology that provides a data readout of the activity of all genes in the genome. By comparing the data from the different groups, the researchers identified which genes show differences in their activity. By organizing and interpreting these genes, the researchers found an overall pattern of commonality between the two diseases. According to the researchers, the hypothesis that the brain experiences a similar response to disparate neurodegenerative diseases has exciting clinical implications. “These findings suggest that a common therapy might be developed to help mitigate the effects of different neurodegenerative diseases of the central nervous system” explained corresponding author Adam Labadorf, PhD, Director of the BU Bioinformatics Hub.

a brainBrains of individuals who died with Huntington’s, Parkinson’s or no neurological condition were analyzed using sequencing technology that provides a data readout of the activity of all genes in the genome. NeuroscienceNews.com image is in the public domain.“Though no such treatment yet exists, this finding will lead to experiments to better understand the specific mechanisms of the inflammatory response in the neurodegenerating brain, which may in turn lead to new treatments.”

Labadorf believes that at present, these findings are too preliminary to suggest new clinical treatments. However, as many anti-inflammatory drugs are already available, there may be a relatively short path to designing clinical trials for drugs that modulate the inflammatory response in people with neurodegenerative disease.

“While these findings are specific to HD and PD, these two diseases are sufficiently distinct to suggest that the observed pattern of differential gene activity may likely be observed in other neurodegenerative diseases of the central nervous system, including Alzheimer’s disease and Chronic Traumatic Encephalophathy (CTE).”

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLEFunding: Funding for this study was provided by grants from US National Institutes of Health (R01-S076843), Characterization of the Role of Cyclin G-associated Kinase in Parkinson Disease, (R01-NS073947), Epigenetic Markers in Huntington’s Disease Brain, (R01-NS088538), An IPSc based platform for functionally assessing genetic and environmental Risk in PD, (U24-NS072026) National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders and the Jerry McDonald Huntington Disease Research Fund.

Source: Gina DiGravio – BMCPublisher: Organized by NeuroscienceNews.com.Image Source: NeuroscienceNews.com image is in the public domain.Original Research: Full open access research for “Evidence for a Pan-Neurodegenerative Disease Response in Huntington’s and Parkinson’s Disease Expression Profiles” by Adam Labadorf, Seung H. Choi, and Richard H. Myers in Frontiers in Molecular Neuroscience. Published online January 11 2017 doi:10.3389/fnmol.2017.00430

CITE THIS NEUROSCIENCENEWS.COM ARTICLEMLAAPACHICAGOBMC “Commonalities in the Brains of People With Huntington’s and Parkinson’s Discovered.” NeuroscienceNews. NeuroscienceNews, 12 January 2018.<http://neurosciencenews.com/huntingtons-parkinsons-brains-8305/>.Abstract

Evidence for a Pan-Neurodegenerative Disease Response in Huntington’s and Parkinson’s Disease Expression Profiles

Huntington’s and Parkinson’s Diseases (HD and PD) are neurodegenerative disorders that share some pathological features but are disparate in others. For example, while both diseases are marked by aberrant protein aggregation in the brain, the specific proteins that aggregate and types of neurons affected differ. A better understanding of the molecular similarities and differences between these two diseases may lead to a more complete mechanistic picture of both the individual diseases and the neurodegenerative process in general. We sought to characterize the common transcriptional signature of HD and PD as well as genes uniquely implicated in each of these diseases using mRNA-Seq data from post mortem human brains in comparison to neuropathologically normal controls. The enriched biological pathways implicated by HD differentially expressed genes show remarkable consistency with those for PD differentially expressed genes and implicate the common biological processes of neuroinflammation, apoptosis, transcriptional dysregulation, and neuron-associated functions. Comparison of the differentially expressed (DE) genes highlights a set of consistently altered genes that span both diseases. In particular, processes involving nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and transcription factor cAMP response element-binding protein (CREB) are the most prominent among the genes common to HD and PD. When the combined HD and PD data are compared to controls, relatively few additional biological processes emerge as significantly enriched, suggesting that most pathways are independently seen within each disorder. Despite showing comparable numbers of DE genes, DE genes unique to HD are enriched in far more coherent biological processes than the DE genes unique to PD, suggesting that PD may represent a more heterogeneous disorder. The complexity of the biological processes implicated by this analysis provides impetus for the development of better experimental models to validate the results.

A new study suggests that an immune response to alpha-synuclein proteins — which accumulate inside the brains of people with Parkinson’s disease — plays a role in the disease. Photo courtesy of Jean Vonsattel, CUMC.

New York, NY (June 21, 2017)—Researchers have found the first direct evidence that autoimmunity—in which the immune system attacks the body’s own tissues—plays a role in Parkinson’s disease, the neurodegenerative movement disorder. The findings raise the possibility that the death of neurons in Parkinson’s could be prevented by therapies that dampen the immune response.

The study, led by scientists at Columbia University Medical Center (CUMC) and the La Jolla Institute for Allergy and Immunology, was published today in Nature.

“The idea that a malfunctioning immune system contributes to Parkinson’s dates back almost 100 years,” said study co-leader David Sulzer, Ph.D., professor of neurobiology (in psychiatry, neurology, and pharmacology) at CUMC. “But until now, no one has been able to connect the dots. Our findings show that two fragments of alpha-synuclein, a protein that accumulates in the brain cells of people with Parkinson’s, can activate the T cells involved in autoimmune attacks.

“It remains to be seen whether the immune response to alpha-synuclein is an initial cause of Parkinson’s or if it contributes to neuronal death and worsening symptoms after the onset of the disease,” said study co-leader Alessandro Sette, Dr. Biol. Sci., professor in the Center for Infectious Disease at La Jolla Institute for Allergy and Immunology in La Jolla, Calif. “These findings, however, could provide a much-needed diagnostic test for Parkinson’s disease and could help us to identify individuals at risk or in the early stages of the disease.”

Scientists once thought that neurons were protected from autoimmune attacks. However, in a 2014 study, Dr. Sulzer’s lab demonstrated that dopamine neurons (those affected by Parkinson’s disease) are vulnerable because they have proteins on the cell surface that help the immune system recognize foreign substances. As a result, they concluded, T cells had the potential to mistake neurons damaged by Parkinson’s disease for foreign invaders.

The new study found that T cells can be tricked into thinking dopamine neurons are foreign by the buildup of damaged alpha-synuclein proteins, a key feature of Parkinson’s disease. “In most cases of Parkinson’s, dopamine neurons become filled with structures called Lewy bodies, which are primarily composed of a misfolded form of alpha-synuclein,” said Dr. Sulzer.

In the study, the researchers exposed blood samples from 67 Parkinson’s disease patients and 36 age-matched healthy controls to fragments of alpha-synuclein and other proteins found in neurons. They analyzed the samples to determine which, if any, of the protein fragments, triggered an immune response. Little immune cell activity was seen in blood samples from the controls. In contrast, T cells in patients’ blood samples, which had been apparently primed to recognize alpha-synuclein from past exposure, showed a strong response to the protein fragments. In particular, the immune response was associated with a common form of a gene found in the immune system, which may explain why many people with Parkinson’s disease carry this gene variant.

Dr. Sulzer hypothesizes that autoimmunity in Parkinson’s disease arises when neurons are no longer able to get rid of abnormal alpha-synuclein. “Young, healthy cells break down and recycle old or damaged proteins,” he said, “but that recycling process declines with age and with certain diseases, including Parkinson’s. If abnormal alpha-synuclein begins to accumulate, and the immune system hasn’t seen it before, the protein could be mistaken as a pathogen that needs to be attacked.”

The Sulzer and Sette labs are now analyzing these responses in additional patients and are working to identify the molecular steps that lead to the autoimmune response in animal and cellular models.

“Our findings raise the possibility that an immunotherapy approach could be used to increase the immune system’s tolerance for alpha-synuclein, which could help to ameliorate or prevent worsening symptoms in Parkinson’s disease patients,” said Dr. Sette.

The study was supported by grants from the JPB Foundation, the William F. Richter Foundation, the Parkinson’s Foundation, the National Institute of Neurological Disorders and Stroke (P50 NS38377), the National Institute on Aging (90071017), and the Michael J. Fox Foundation for Parkinson’s Research.

Columbia University filed a patent application for use of alpha-synuclein peptides as biomarkers (US Patent Application No. 15/300,713). David Sulzer (CUMC) and Alessandro Sette (La Jolla Institute) are listed as inventors. The authors declare no other conflicts of interest. ###

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.edu or columbiadoctors.org.

3 Mineral Waters That Can Remove Aluminum from the Brain by PAUL FASSA

aluminumpoisoningheadThere has been a dramatic increase in neurological diseases linked to aluminum toxicity. The blood brain barrier doesn’t stop aluminum’s intrusion into our gray matter. Aluminum accumulates and remains in tissue that doesn’t have a rapid cellular turnover.

Apoptosis is the natural cell death and replacement process that occurs throughout the body, excluding cancer cells. Cancer cells keep reproducing and colonizing into tumors unless apoptosis is introduced or the cells are outright killed from chemical compounds, both natural and synthetic.

Aluminum accrues to toxic levels over time in slow apoptotic cell turnover tissues, such as bone matter, the heart and the brain. The brain and its associated nervous system is where diseases such as Alzheimer’s, Parkinson’s, MS, chronic fatigue and other neurological or auto-immune diseases manifest, including the complete autistic spectrum, from learning disorders to full blown autism.

There is no shortage of aluminum toxins in our environment. It’s in cookware, beverage containers, foil, cigarette smoke, cosmetics, antiperspirants, sunscreen, antacids, and those ubiquitous chemtrails that most ignore from which aluminum nanoparticles can be breathed into our lungs and routed directly into our blood or through the sinuses into our brains.

Aluminum is in all vaccines. Injecting aluminum bypasses the possibility of eliminating it through normal channels. Straight into the blood it goes to be carried into the brain and heart, adding to their accumulated aluminum toxicity loads.

According to Dr. Chris Exley, PhD, we have come into the aluminum age. Many trolling commentators love to explain how aluminum is the must common mineral on the planet and therefore it’s harmless. Dr. Exley has dedicated over two decades of his scientific life to researching aluminum toxicity. He calls the period of time from the early 20th Century to now the “Age of Aluminum.”

Before then, aluminum remained in the ground as the most abundant mineral in earth that hadn’t yet been mined. Dr. Exley claims mining aluminum and using it in so many ways corresponds to the marked increase of neurological diseases.

Dr. Chris Exley’s Message to the 2011 Vaccine Safety Conference

A key aspect of his conference delivery concerned helping vaccinated kids improve their neurological damage. Ironically, it involves the second most abundant mineral in mother earth – silica. Exley has put kids who had autism spectrum disorders or other neurological damage from vaccinations on a form of silica known as silicic acid with excellent results.

Silicic acid is basically oxygenated silica. Exley considers this the best and most bio-available way to get silica through the gut and into the blood, then into brain matter where it binds with the aluminum molecules and leads them out of brain cell tissue safely through the urine.

He had used a Malasysian mineral water called Spritzer on aluminum toxic children suffering from autism spectrum disorders with significant success. Aluminum is in almost all vaccines. Later he and his team had 15 Alzheimer’s disease (AD) patients use that water at the same rate of one liter per day for 13 weeks.

Aluminum levels were lower by anywhere from 50 to 70 percent in all the subjects involved, and of the 15 AD patients, eight no longer deteriorated and three actually showed substantial cognitive increase. Perhaps coconut oil is better for reversing AD, but mineral waters high in Orthosilicic or ionic silicic acid will reduce aluminum toxicity in the brain to help ward off AD.

The more USA accessible mineral waters with similar levels of silicic acid to Spritzer, which can volvic-water-triopenetrate the blood-brain barrier, are Volvic and Fiji. My personal favorite is Fiji because it has the highest level of ionic suspended silica as silicic acid and is the least expensive. I’ve seen it in WalMart at $1.99 per liter.

Also, People’s Chemist Shane Ellison analyzed various water bottles and said Fiji water bottles are free of BPA and “its chemical cousins”. Others he rates highly as BPA free are Voss, Evian, and Smart Water.

The suggested protocol is at least five days consuming a 1.5 liter bottle of water daily. More is required for high levels of aluminum toxicity. Dr. Exley considers drinking the whole bottle within an hour as the most efficient method of detoxing aluminum from the brain.

fiji waterDr. Exley explains that there are three commercial bottled waters listing silica amounts as milligrams (mg) per liter on the bottle. Fiji has the highest amount of the three. Neither of us is affiliated with Fiji.

Silica mineral waters can be supplemented to help prevent dementia. Obviously it can also be used as an adjunct with pure cold pressed coconut oil to stop early onset Alzheimer’s or even reverse most of the symptoms after AD symptoms appear. More on coconut oil for Alzheimer’s can be found here.

Aluminum (Al) is passed out through the urine when one supplements silica sufficiently. It seems there’s little danger of taking too much, as long as adequate water is consumed and vitamin B1 and potassium levels are maintained.

More About Silica

Silica helps ensure collagen elasticity of all connecting tissues in the body, including tendons and cartilage. This reduces aches and pains and maintains your body’s flexibility. It has also been determined that high levels of blood serum silica keep arterial plaque from building and clogging blood vessels.

A major culprit for arterial plaque has recently shifted from cholesterol buildup to arterial calcification from serum calcium that is not absorbed as bone matter. It’s known that silica is an important part of building bone matter.

Without sufficient silica, magnesium, and vitamin K2, calcium doesn’t become part of bone matter and remains in the blood to potentially calcify in the soft tissue of inner artery walls and the heart.

Silica is vital for keeping strong bones and a healthy cardiovascular system. This qualifies silica as an essential anti-aging mineral that is much more than a skin deep beauty mineral. Other good sources of silica are the herb horsetail, cucumbers, and diatomaceous earth powder.

Although these three other sources are helpful for the recent aforementioned reasons, they lack the ionic suspension of silicic acid found in the mineral waters to penetrate the blood-brain barrier. I just found these other sources for ionic silica or silicic acid as well, here and here.

Paul Fassa is a contributing staff writer for REALfarmacy.com. His pet peeves are the Medical Mafia’s control over health and the food industry and government regulatory agencies’ corruption. Paul’s valiant contributions to the health movement and global paradigm shift are world renowned. Visit his blog by following this link and follow him on Twitter here.

Summary: University of Texas researchers report neurons in the mouse brain tend to surge at the equivalent of human age 40. During this period, interleukin33 also surges in healthy mice. In those lacking the gene, neurodegeneration occurred, eventually resulting in dementia.Source: UT Health Science Center Houston.Researchers at The University of Texas Health Science Center at Houston (UTHealth) School of Dentistry and McGovern Medical School have discovered a previously unknown characteristic of brain-cell aging that could help detect late-onset Alzheimer’s disease decades before symptoms begin.The study, “Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice,” appeared online in the journal Translational Psychiatry earlier this year.Working with mice, the UTHealth team found that neurons in the brain experienced a sudden increase in aging around the mouse equivalent of age 40 in humans. Normal mice responded with a surge of interleukin33, a protein that activates the body’s repair mechanisms to make the neurons healthy again. Mice lacking the IL33 gene didn’t experience the surge and continued to decline, eventually developing dementia at an age roughly equivalent to 68 in humans.“We think we’re getting old gradually, but when we’re talking about these cells, we’ve discovered that it’s not that way,” said Yahuan Lou, Ph.D., a professor in the Department of Diagnostic and Biomedical Sciences at the School of Dentistry.Late-onset sporadic Alzheimer’s disease occurs after age 65 and represents approximately 95 percent of all cases, with the other 5 percent believed to be genetic. By the time symptoms appear, the brain has already lost massive numbers of neurons. The UTHealth researchers believe the surge at age 40 may be an ideal time to look for biomarkers that predict Alzheimer’s long before the damage begins.Lou first detected the power of IL33 while studying premature ovarian failure in mice. “We observed that when we removed IL33, the ovary shrank much faster than normal. So we wondered: If IL33 does this in the ovary, what does it do in the brain? The brain has an abundance of IL33.”Looking for collaborators who could test that question, Lou was surprised to learn that researchers from McGovern Medical School’s Department of Psychiatry and Behavioral Sciences had recently moved into the new UT Behavioral and Biomedical Sciences Building that he and other dental school researchers had also newly occupied. Among his new neighbors were Department of Psychiatry Professor Joao De Quevedo, M.D., Ph.D., and Assistant Professor Ines Moreno-Gonzalez, Ph.D., of the Mitchell Center for Alzheimer’s Disease, who had the expertise and resources for analyzing rodent behavior and correlating it to humans. A collaborative team soon formed, and their mouse study led to the paper in Translational Psychiatry with plans for follow-up studies to explore the tantalizing results.

Late-onset sporadic Alzheimer’s disease occurs after age 65 and represents approximately 95 percent of all cases, with the other 5 percent believed to be genetic. By the time symptoms appear, the brain has already lost massive numbers of neurons. The UTHealth researchers believe the surge at age 40 may be an ideal time to look for biomarkers that predict Alzheimer’s long before the damage begins. NeuroscienceNews.com image is in the public domain.

Lou said a group of researchers in Singapore recently conducted an experiment using mice that model familial early-onset Alzheimer’s disease. “When they injected IL33 into the [Alzheimer’s] mice, they saw that the plaque load was reduced, but they didn’t know why,” he said. “We’ve figured out why.”

The IL33 injections seemed to relieve symptoms temporarily, he added, but did not cure the disease. The effects lasted about two weeks in mice — equal to several months in humans. Lou believes finding a way to enhance the brain’s own supply of IL33 may lead to potential treatments for the disease.

The cause of late-onset Alzheimer’s is a medical mystery with many potential causes under investigation, including neuro-inflammation, abnormal aging, smoking, and infections. IL33 deficiency is another promising lead, with additional studies planned as funding is secured.

Late-onset Alzheimer’s disease (AD) remains a medical mystery. Recent studies have linked it to impaired repair of aged neurons. Potential involvement of interleukin33 (IL33) in AD has been reported. Here we show that IL33, which was expressed by up to 75% astrocytes in the aged brains, was critical for repair of aged neurons. Mice lacking Il33 gene (Il33−/−) developed AD-like disease after 60–80 weeks, which was characterized by tau abnormality and a heavy loss of neurons/neurites in the cerebral cortex and hippocampus accompanied with cognition/memory impairment. We detected an abrupt aging surge in the cortical and hippocampal neurons at middle age (40 weeks). To counter the aging surge, wild-type mice rapidly upregulated repair of DNA double-strand breaks (DSBs) and autophagic clearance of cellular wastes in these neurons. Il33−/− mice failed to do so, but instead went on to develop rapid accumulation of abnormal tau, massive DSBs and abnormal autophagic vacuoles in these neurons. Thus, uncontrolled neuronal aging surge at middle age due to lack of IL33 resulted in neurodegeneration and late-onset AD-like symptom in Il33−/− mice. Our study also suggests that the aging surge is a time to search for biomarkers for early diagnosis of AD before massive neuron loss.

Image: Dheeraj Roy, Tonegawa Lab/MITFULL SCREENA high magnification image shows hippocampal CA3 memory engram cells (red). One day after learning, memory recall tests are performed and the recall-induced activated CA3 cells are shown in green staining. The red CA3 engram cells that are also green (i.e., yellow by overlap) represent engram cells that have been reactivated during memory recall.A high magnification image shows hippocampal CA3 memory engram cells (red). One day after learning, memory recall tests are performed and the recall-induced activated CA3 cells are shown in green staining. The red CA3 engram cells that are also green (i.e., yellow by overlap) represent engram cells that have been reactivated during memory recall.

Learning and memory are generally thought to be composed of three major steps: encoding events into the brain network, storing the encoded information, and later retrieving it for recall.Two years ago, MIT neuroscientists discovered that under certain types of retrograde amnesia, memories of a particular event could be stored in the brain even though they could not be retrieved through natural recall cues. This phenomenon suggests that existing models of memory formation need to be revised, as the researchers propose in a new paper in which they further detail how these “silent engrams” are formed and re-activated.The researchers believe their findings offer evidence that memory storage does not rely on the strengthening of connections, or “synapses,” between memory cells, as has long been thought. Instead, a pattern of connections that form between these cells during the first few minutes after an event occurs are sufficient to store a memory.“One of our main conclusions in this study is that a specific memory is stored in a specific pattern of connectivity between engram cell ensembles that lie along an anatomical pathway. This conclusion is provocative because the dogma has been that a memory is instead stored by synaptic strength,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, the director of the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, and the study’s senior author.The researchers also showed that even though memories held by silent engrams cannot be naturally recalled, the memories persist for at least a week and can be “awakened” days later by treating cells with a protein that stimulates synapse formation.Dheeraj Roy, a recent MIT PhD recipient, is the lead author of the paper, which appears in the Proceedings of the National Academy of Sciences the week of Oct. 23. Other authors are MIT postdoc Shruti Muralidhar and technical associate Lillian Smith.Silent memoriesNeuroscientists have long believed that memories of events are stored when synaptic connections, which allow neurons to communicate with each other, are strengthened. Previous studies have found that if synthesis of certain cellular proteins is blocked in mice immediately after an event occurs, the mice will have no long-term memory of the event.However, in a 2015 paper, Tonegawa and his colleagues showed for the first time that memories could be stored even when synthesis of the cellular proteins is blocked. They found that while the mice could not recall those memories in response to natural cues, such as being placed in the cage where a fearful event took place, the memories were still there and could be artificially retrieved using a technique known as optogenetics.The researchers have dubbed these memory cells “silent engrams,” and they have since found that these engrams can also be formed in other situations. In a study of mice with symptoms that mimic early Alzheimer’s disease, the researchers found that while the mice had trouble recalling memories, those memories still existed and could be optogenetically retrieved.In a more recent study of a process called systems consolidation of memory, the researchers found engrams in the hippocampus and the prefrontal cortex that encoded the same memory. However, the prefrontal cortex engrams were silent for about two weeks after the memory was initially encoded, while the hippocampal engrams were active right away. Over time, the memory in the prefrontal cortex became active, while the hippocampal engram slowly became silent.In their new PNAS study, the researchers investigated further how these silent engrams are formed, how long they last, and how they can be re-activated.Similar to their original 2015 study, they trained mice to fear being placed in a certain cage, by delivering a mild foot shock. After this training, the mice freeze when placed back in that cage. As the mice were trained, their memory cells were labeled with a light-sensitive protein that allows the cells to be re-activated with light. The researchers also inhibited the synthesis of cellular proteins immediately after the training occurred.They found that after the training, the mice did not react when placed back in the cage where the training took place. However, the mice did freeze when the memory cells were activated with laser light while the animals were in a cage that should not have had any fearful associations. These silent memories could be activated by laser light for up to eight days after the original training.Making connectionsThe findings offer support for Tonegawa’s new hypothesis that the strengthening of synaptic connections, while necessary for a memory to be initially encoded, is not necessary for its subsequent long-term storage. Instead, he proposes that memories are stored in the specific pattern of connections formed between engram cell ensembles. These connections, which form very rapidly during encoding, are distinct from the synaptic strengthening that occurs later (within a few hours of the event) with the help of protein synthesis.“What we are saying is that even without new cellular protein synthesis, once a new connection is made, or a pre-existing connection is strengthened during encoding, that new pattern of connections is maintained,” Tonegawa says. “Even if you cannot induce natural memory recall, the memory information is still there.”This raised a question about the purpose of the post-encoding protein synthesis. Considering that silent engrams are not retrieved by natural cues, the researchers believe the primary purpose of the protein synthesis is to enable natural recall cues to do their job efficiently.The researchers also tried to reactivate the silent engrams by treating the mice with a protein called PAK1, which promotes the formation of synapses. They found that this treatment, given two days after the original event took place, was enough to grow new synapses between engram cells. A few days after the treatment, mice whose ability to recall the memory had been blocked initially would freeze after being placed in the cage where the training took place. Furthermore, their reaction was just as strong as that of mice whose memories had been formed with no interference.Sheena Josselyn, an associate professor of psychology and physiology at the University of Toronto, said the findings run counter to the longstanding idea that memory formation involves strengthening of synapses between neurons and that this process requires protein synthesis.“They showed that a memory formed during protein-synthesis inhibition may be artificially (but not naturally) recalled. That is, the memory is still retained in the brain without protein synthesis, but this memory cannot be accessed under normal conditions, suggesting that spines may not be the key keepers of information,” says Josselyn, who was not involved in the research. “The findings are controversial, but many paradigm-shifting papers are.”Along with the researchers’ previous findings on silent engrams in early Alzheimer’s disease, this study suggests that re-activating certain synapses could help restore some memory recall function in patients with early stage Alzheimer’s disease, Roy says.The research was funded by the RIKEN Brain Science Institute, the Howard Hughes Medical Institute, and the JPB Foundation.

Summary: Researchers have invented a probe that lights up when it binds to a misfolded amyloid peptide.

Source: Rice University.

A probe invented at Rice University that lights up when it binds to a misfolded amyloid beta peptide — the kind suspected of causing Alzheimer’s disease — has identified a specific binding site on the protein that could facilitate better drugs to treat the disease.

Even better, the lab has discovered that when the metallic probe is illuminated, it catalyzes oxidation of the protein in a way they believe might keep it from aggregating in the brains of patients.

The study done on long amyloid fibrils backs up computer simulations by colleagues at the University of Miami that predicted the photoluminescent metal complex would attach itself to the amyloid peptide near a hydrophobic (water-avoiding) cleft that appears on the surface of the fibril aggregate. That cleft presents a new target for drugs.

Finding the site was relatively simple once the lab of Rice chemist Angel Martí used its rhenium-based complexes to target fibrils. The light-switching complex glows when hit with ultraviolet light, but when it binds to the fibril it becomes more than 100 times brighter and causes oxidation of the amyloid peptide.

“It’s like walking on the beach,” Marti said. “You can see that someone was there before you by looking at footprints in the sand. While we cannot see the rhenium complex, we can find the oxidation (footprint) it produces on the amyloid peptide.

“That oxidation only happens right next to the place where it binds,” he said. “The real importance of this research is that allows us to see with a high degree of certainty where molecules can interact with amyloid beta fibrils.”

The study appears in the journal Chem.

“We believe this hydrophobic cleft is a general binding site (on amyloid beta) for molecules,” Martí said. “This is important because amyloid beta aggregation has been associated with the onset of Alzheimer’s disease. We know that fibrillar insoluble amyloid beta is toxic to cell cultures. Soluble amyloid oligomers that are made of several misfolded units of amyloid beta are also toxic to cells, probably even more than fibrillar.

“There’s an interest in finding medications that will quench the deleterious effects of amyloid beta aggregates,” he said. “But to create drugs for these, we first need to know how drugs or molecules in general can bind and interact with these fibrils, and this was not well-known. Now we have a better idea of what the molecule needs to interact with these fibrils.”

When amyloid peptides fold properly, they hide their hydrophobic residues while exposing their hydrophilic (water-attracting) residues to water. That makes the proteins soluble, Martí said. But when amyloid beta misfolds, it leaves two hydrophobic residues, known as Valine 18 and Phenylalanine 20, exposed to create the hydrophobic cleft.

“It’s perfect, because then molecules with hydrophobic domains are driven to bind there,” Martí said. “They are compatible with this hydrophobic cleft and associate with the fibril, forming a strong interaction.”

Image shows monkey brain scans A rhenium-based complex developed at Rice University binds to fibrils of misfolded amyloid beta peptide, which marks the location of a hydrophobic cleft that could serve as a drug target, and oxidizes the fibril, which changes its chemistry in a way that could prevent further aggregation. NeuroscienceNews.com image is credited to Martí Group/Rice University. If the resulting oxidation keeps the fibrils from aggregating farther into the sticky substance found in the brains of Alzheimer’s patients, it may be the start of a useful strategy to stop aggregation before symptoms of the disease appear.

“It’s a very attractive system because it uses light, which is a cheap resource,” Martí said. “If we can modify complexes so they absorb red light, which is transparent to tissue, we might be able to perform these photochemical modifications in living animals, and maybe someday in humans.”

He said light activation allows the researchers to have “exquisite control” of oxidation.

“We imagine it might be possible someday to prevent symptoms of Alzheimer’s by targeting amyloid beta in the same way we treat cholesterol in people now to prevent cardiovascular disease,” Martí said. “That would be wonderful.”

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

The Welch Foundation and National Science Foundation supported the research. The Center of Computational Science at the University of Miami provided computational resources. Source: David Ruth – Rice University Publisher: Organized by NeuroscienceNews.com. Image Source: NeuroscienceNews.com image is credited to Martí Group/Rice University. Original Research: Abstract for “Photochemical Identification of Molecular Binding Sites on the Surface of Amyloid-β Fibrillar Aggregates” by Amir Aliyan, Thomas J. Paul, Bo Jiang, Christopher Pennington, Gaurav Sharma, Rajeev Prabhakar, and Angel A. Martí in Chem. Published online October 19 2017 doi:10.1016/j.chempr.2017.09.011

The Bigger Picture Alzheimer’s disease is a form of dementia affecting over 44 million people worldwide, and its symptoms include agitation, confusion, and memory loss. This disease is characterized by aggregates of the amyloid-β (Aβ) peptide in the brain. The transition of Aβ from the soluble to the aggregated form is linked to the onset of Alzheimer’s disease. Molecules that inhibit Aβ aggregation or quench its harmful effect are highly sought after. However, how molecules bind to Aβ is still uncertain. Aβ aggregates are disordered in nature, preventing the use of common methods for studying structure and binding. To address this, we used a rhenium complex that binds to Aβ. Upon light exposure, this complex produces oxidation on Aβ, leaving a mark at the place of binding. Spectroscopic and computational studies allowed elucidation of locations and binding modes of these molecules on Aβ. This information will guide the production of potent drugs with better binding affinities to Aβ for the treatment of Alzheimer’s disease.

Summary The aggregation of amyloid-β (Aβ) into insoluble fibrils has been associated with the development of Alzheimer’s disease. The study of Aβ aggregation with [Re(CO)3(dppz)(Py)]+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine; Py = pyridine) has led to the observation of an irradiation-induced light-switching response accompanied by the oxidation of the Aβ fibril. Here, we used the photophysical and photochemical properties of this complex, as well as spectroscopic and computational methods, to elucidate molecular binding sites on Aβ fibrils. [Re(CO)3(dppz)(Py)]+ binds to Aβ fibrils with a dissociation constant of 4.2 μM and a binding stoichiometry 2.8:1 (Aβ/complex). Molecular dynamics (MD) simulations predicted binding of [Re(CO)3(dppz)(Py)]+ through a hydrophobic cleft on the fibril axis between Val18 and Phe20. Tandem mass spectrometry analysis indicated that oxidation occurred at Met35, footprinting the place of binding, which is close to the site predicted by the MD simulations. Finding binding sites in Aβ is of great importance for the design of Aβ-binding drugs.

Lyme disease is exceedingly difficult to treat, due to its well-known shape-shifting (pleomorphic) abilities, with conventional antibiotics often failing to produce a long-term cure. Could the commonly used natural plant Stevia provide a safer, and more effective means to combat this increasingly prevalent infection?

A promising new preclinical study has revealed that whole stevia leaf extract possesses exceptional antibiotic activity against the exceedingly difficult to treat pathogen Borrelia Burgdorferi known to cause Lyme disease. The study found,

Stevia whole leaf extract, as an individual agent, was effective against all known morphological forms of B. burgdorferi.”

At present, the CDC acknowledges that at least 300,000 are infected with Lyme disease, annually, with the conventional standard of care relying on antibiotics that are not only toxic but increasingly coming under scrutiny for addressing only surface aspects of the infection, often leaving antibiotic-resistance Lyme disease deep within the system to continue to cause harm.

burgdorferi has a complex life cycle, and can exist in radically different forms: spirochetes, spheroplast (or L-form which lacks a cell wall), round bodies or cyst form (which allows for dormancy and escaping PCR detection), and highly antibiotic-resistant biofilms. This pleomorphic property makes conventional treatment exceptionally difficult because while some conventional antibiotics are effective against forms with a cell wall such as spirochetes, they are ineffective against those without a cell wall. This enables B. burgdorferi to change form to evade eradication through conventional means. Also, biofilm formation creates a significant barrier against most conventional antibiotics, even when used in combination, and has been recently suggested to be the most effective mechanism of resistance.

The researchers directly compared an alcohol extract of a whole stevia leaf product commonly found on the U.S. retail market to conventional antibiotics, and assessed their respective abilities to kill the various forms of Borrelia burgdorferi, including so called “persister” forms.

The study pointed out that, according to the CDC, about 10-20% of Lyme disease patients treated with antibiotics for the recommended 2-4 weeks experience adverse health effects, such as fatigue, pain, or joint and muscle aches. In some of these patients, the adverse effects last for more than 6 months. These patients are often labeled with “chronic Lyme disease,” or “post treatment Lyme disease syndrome.” While the adverse effects of antibiotics, including their destruction of beneficial microbes in the gut, may account for this syndrome, another possibility is that the drugs drive antibiotic-resistant forms of the disease deeper into the system, resulting in enhanced disease-associated malaise.

Given the well-known challenges of eradicating B. burgdorferi through conventional antibiotics, the researchers explored the potential for stevia as an antimicrobial.

Stevia is not normally considered an anti-microbial agent, but all plants possess in-built phytochemical defense systems which protect them against infection, and which by consuming them, we ourselves can sometimes harness and benefit from. The researchers elaborate on this point:

The leaf extract of Stevia possesses many phytochemicals, which include austroinullin, β-carotene, dulcoside, nilacin, rebaudi oxides, riboflavin, steviol, stevioside, and tiamin with known antimicrobial properties against many pathogens [40, 42, 43]. The role of these compounds is mainly to protect the plant from microbial infection and adverse environmental conditions [38–43].”

The researchers explored Stevia’s potential effectiveness against B. burgdorferi cultures, comparing it to three common antibiotics sometimes used to treat Lyme’s disease: doxycycline, cefoperazone, daptomycin, as well as their combination.

The study results were summarized as follows:

The susceptibility of the different forms was evaluated by various quantitative techniques in addition to different microscopy methods. The effectiveness of Stevia was compared to doxycycline, cefoperazone, daptomycin, and their combinations. Our results demonstrated that Stevia had significant effect in eliminating B. burgdorferi spirochetes and persisters. Sub-culture experiments with Stevia and antibiotics treated cells were established for 7 and 14 days yielding, no and 10% viable cells, respectively compared to the above-mentioned antibiotics and antibiotic combination. When Stevia and the three antibiotics were tested against attached biofilms, Stevia significantly reduced B. burgdorferi forms. Results from this study suggest that a natural product such as Stevia leaf extract could be considered as an effective agent against B. burgdorferi.”

Notably, the study found that the most antibiotic resistant form of B. burgdorferi, the biofilm form, actually increased in mass when individual antibiotics were administered. Stevia, on the other hand, reduced the biofilm mass on both tested surfaces (plastic and collagen) by about 40%.

It is also interesting to note that the stevoside extract, by itself, was not found to be an effective antimicrobial agent against B. burgdorferi; nor did it have any effect on resistant cells. Mass market stevia products, including Coca-cola’s Truvia (ironic branding, considering it does not have the truly therapeutic property of whole stevia), would not, therefore, have the medicinal property associated with the whole herb extract. This speaks, of course, to the well known principle in natural medicine that the activity of the whole can not be reproduced through a part, nor is the therapeutic activity of the whole identical to that of the sum of its parts.

While this is only a preliminary study and should not be interpreted to mean the consumption of whole stevia extract will result in clinical improvements comparable or superior to conventional antibiotics, it opens the door to future research on the topic. That said, anyone who is considering natural ways to prevent Lyme’s disease infection, or to support as an adjunct therapy conventional treatments of the disease, could utilize this safe, food-based substance as a potential means of support and synergy. Certainly, there is little if any indication that stevia could cause harm, unlike conventional treatments. See our stevia research section here for more information.

For more research on natural interventions for Lyme’s disease visit our research page on the topic: Lyme disease research.

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Blueberries may improve attention in children following double-blind trialOctober 13, 2017Blueberries may improve attention in children following double-blind trialCredit: University of ReadingPrimary school children could show better attention by consuming flavonoid-rich blueberries, following a study conducted by the University of Reading.In a paper published in Food & Function, a group of 7-10 year olds who consumed a drink containing wild blueberries or a matched placebo and were tested on their speed and accuracy in completing an executive task function on a computer.The double blind trial found that the children who consumed the flavonoid-rich blueberry drink had 9% quicker reaction times on the test without any sacrifice of accuracy. In particular, the effect was more noticeable as the tests got harder.Professor Claire Williams, a neuroscience professor at the University of Reading said:“This is the first time that we have seen the positive impact that flavonoids can have on the executive function of children. We designed this double blind trial especially to test how flavonoids would impact on attention in young people as it’s an area of cognitive performance that hasn’t been measured before.“We used wild blueberries as they are rich in flavonoids, which are compounds found naturally in foods such as fruits and their juices, vegetables and tea. They have been associated with a range of health benefits including antioxidant and anti-inflammatory effects, and our latest findings continue to show that there is a beneficial cognitive effect of consuming fruit and vegetables, tea, coffee and even dark chocolate which all contain flavonoids.”The children were then asked to pay attention to an array of arrows shown on a PC screen and press a key corresponding to the direction that the central arrow was facing. The task was repeated over a number of trials, where cognitive demand was manipulated by varying how quickly the arrows appeared, whether there were additional arrows appearing either side of the central arrow, and whether the flanking arrows were pointing in the same/different direction as the central arrow.Previous Reading research has shown that consuming wild blueberries can improve mood in children and young people, simple memory recall in primary school children, and that other flavonoid rich drinks such as orange juice can also improve memory and concentration.The Wild Blueberry Association of North America provided a freeze-dried powder made from wild blueberries which was used in the study but did not provide any additional financial support and did not play a role in the design of the study.Wild blueberries are grown and harvested in North America, and are smaller than regular blueberries, and are higher in flavonoids compared to regular varieties.The double-blind trial used a flavonoid-rich wild blueberry drink, with a matched placebo contained 8.9g of fructose, 7.99g of glucose and 4 mg of vitamin C matching the levels of nutrients found in the blueberry drink.The amount of fructose is akin to levels found in a standard pear.This was an executive function task- requiring participants to pay attention to stimuli appearing on screen and responding correctly. The task was a simple one- responding to the direction of an arrow in the middle of a screen (by pressing left/right arrow key) but we then varied how quickly the stimuli appeared, whether there were additional arrows appearing either side of the stimuli and whether those flanking arrows were pointing in the same/different direction as the direction you had to respond.There are 6 main classes of flavonoids:Anthocyanins – found in berry fruits such as the blueberries used in this study and also in red wine.Flavonols – found in onions, leeks, and broccoliFlavones – found in parsley and celery,Isoflavones – found in soy and soy products,Flavanones – found in citrus fruit and tomatoesFlavanols—found in green tea, red wine, and chocolateExplore further: Wild blueberries could boost primary schoolchildren’s memory and concentrationMore information: A. R. Whyte et al. The effect of cognitive demand on the performance of an executive function task following wild blueberry supplementation in 7 to 10 years old children, Food Funct. (2017). DOI: 10.1039/c7fo00832ePeter Anderson. Assessment and Development of Executive Function (EF) During Childhood, Child Neuropsychology (2003). DOI: 10.1076/chin.8.2.71.8724

Researchers from the Bedfordshire Centre for Mental Health Research in association with the University of Cambridge, University of Cincinnati, Carrick Institute, Plasticity Brain Centers and Harvard Macy– MGH Institutes studied whether head-eye vestibular motion (HEVM) therapy is associated with decreased symptoms and increased function in post concussive syndrome patients who have been severely impaired for greater than 6 months after a mild traumatic brain injury.

The investigators reviewed the medical records of 620 post-concussive patients exhibiting Post Concussive Syndrome. The inclusion criteria included only individuals who had sustained a sport-related concussion, had persistent and debilitating symptoms for greater than 6 months, and who had not responded to prior interventions. The selection of subjects based upon the defined criteria yielded a population sample of 70 patients.

As described in the text, each patient was assessed individually, utilizing instrumentation designed to measure and quantify over 40 variables such as symptoms, cognitive function, reaction time, vestibular-ocular function, gaze-holding, and eye-tracking.

The treatments that were administered consisted of the following five components, over a 5-day “intensive” period:

Head-Eye Vestibular Movements (HEVM) performed 5 times per day.

Head-Hand-Eye Coordination Movements performed 3 times per day.

Vestibular-Only Therapies in a Multi-Axis Rotational Chair (MARC) were termed Head-Eye performed twice per day.

After a statistical analysis of these data, the researchers concluded that after 5 days of intensive treatment at their international brain rehabilitation center, there was a significant and substantial change in symptoms of individuals that had been diagnosed with refractory post-concussion syndrome related to a sports-injuries.

The authors also noted a few points of interest:

The pre-treatment symptom scores did not predict how well someone would perform after treatment. This means that pre-existing symptoms did not correlate with post-treatment results. So patients with very severe symptoms did not have any worse results than those with mild symptoms.

Irritability and sleep disturbances were the largest predictors of overall symptoms. It is uncertain whether this means that higher symptoms make people more irritable and less able to sleep soundly, or if people with irritability and difficulty sleeping have higher symptoms.

There was a remarkable improvement in symptoms associated with mental health, such as irritability.

A 5-day intensive therapy scenario involving patient-specific vestibular, ocular, sensory, and physical therapies demonstrated to be an effective modality that might be considered in chronic treatment refractory PCS.

Widely accepted research suggests that Approximately 1.8–3.6 million annual traumatic brain injuries occur in the United States. Published research has demonstrated that the majority of symptoms that are associated with concussions resolve on their own within 14-30 days.

However, in about 10% of all cases the symptoms experienced after sustaining a head trauma enter a “chronic”phase, in which symptoms may persist for weeks, to months, or even permanently. Once symptoms are experienced for greater than three months, a patient may be diagnosed with post-concussion syndrome.

Summary: Researchers at UT Southwestern report medications used to treat arthritis and lung cancer may help in the battle against glioblastoma.

Source: UT Southwestern.

A new strategy for treating brain tumors may extend or save the lives of patients diagnosed with one of the deadliest forms of cancer, according to a study from UT Southwestern Medical Center.

The research demonstrates in mice that a combination of medications – traditionally used separately to treat lung cancer and arthritis – can destroy glioblastoma, a difficult-to-treat brain tumor that is lethal to most patients in little more than a year.

The combination of these medications disables two proteins responsible for helping the cancer cells survive, providing a therapy that UT Southwestern is working to fast-track for clinical use.

“This could be a groundbreaking treatment. If it works in patients, then it will be an important advance,” said Dr. Amyn Habib, a member of UT Southwestern’s Peter O’Donnell Jr. Brain Institute and the Harold C. Simmons Comprehensive Cancer Center.

The research published in Nature Neuroscience answers a decades-old question of why a treatment that disables a protein common in various cancers has been effective in some forms of lung and colon cancer but not in glioblastoma.

The protein, known as epidermal growth factor receptor (EGFR), resides in the tumor cell’s membrane and has been a traditional target for fighting malignant tumors. Dr. Habib’s team found that when doctors use a medication to disable the receptor, a second protein is produced in the brain that takes over the receptor’s function to keep the cancer cell alive.

The study shows that blocking both the receptor and the tumor necrosis factor (TNF) destroys the glioma tumors.

The medications used to disable these proteins are already approved by the U.S. Food and Drug Administration, including TNF inhibitors used to treat arthritis and other rheumatologic conditions. Dr. Habib said this could speed the effort at UT Southwestern to organize a clinical trial to test the treatment on lung cancer and glioblastoma patients.

“This is a terrific example of research that can be relatively quickly carried into the clinic,” said Dr. Habib, Associate Professor of Neurology & Neurotherapeutics.

Glioblastoma is the most lethal and common type of brain cancer, accounting for 17 percent of malignant brain tumors. The disease aggressively spreads through the brain and can prove fatal within months, though surgery, chemotherapy, and radiation treatments can often help patients survive more than a year.

UT Southwestern is testing an array of other approaches to improve the prognosis for patients, from protein-inhibiting medications to immunotherapy that uses the body’s immune system to fight cancer.

Dennis Kothmann, a retired math teacher with glioblastoma, hopes one of these approaches will work for him. While Dr. Habib’s treatment strategy is still being prepared for clinical use, Mr. Kothmann is participating in an immunotherapy clinical trial at UT Southwestern.

“Chemo hasn’t worked very well for other people with this disease,” he explained as a nurse prepared to deliver his latest infusion through his arm. “Why not try something different, give yourself a chance?”

The 71-year-old Fort Worth native was diagnosed with glioblastoma in November after seeking medical treatment for his headaches and vision problems. Mr. Kothmann tells his story with an inspiring air of positivity, his jovial smile belying the grim prospects for beating such a disease.

“There’s no sense in getting down,” Mr. Kothmann said, his wife Candace nodding in agreement next to him. “That’s not going to make me better.”

glioblastoma tumors Imaging shows how a new treatment strategy gradually eliminated malignant brain tumors in mice. The images were taken every 10 days, with the tumor no longer visible after 20 days. UT Southwestern is working to fast-track the treatment for clinical use. NeuroscienceNews.com image is credited to UT Southwestern. Dr. Habib is encouraged by the initial success of his protein-disabling strategy. But he acknowledges a cure may not be imminent because cancers tend to adapt to treatments and find other pathways to thrive if one is blocked.

For example, disabling the EGFR protein initially showed success in lung cancer patients, but over time the cells develop resistance to the medication.

“But if we can provide a remission or slowing of the disease and extend survival, that’s a big advance in fighting this devastating disease,” said Dr. Habib, also a staff physician at the North Texas VA Medical Center.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE The study was supported by the National Institutes of Health, the Office of Medical Research, and Department of Veterans Affairs. Other collaborators at UT Southwestern include Dr. Gao Guo, a postdoctoral researcher in Dr. Habib’s laboratory, and Dr. Edward Pan, Associate Professor of Neurology & Neurotherapeutics, Neurological Surgery, Dr. Sandeep Burma, Associate Professor of Radiation Oncology, Dr. Kimmo Hatanpaa, Associate Professor of Pathology, Dr. Bruce Mickey, Vice Chairman and Professor of Neurosurgery, and Dr. David Wang, Associate Professor of Internal Medicine.

The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 47 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site.

Aberrant epidermal growth factor receptor (EGFR) signaling is widespread in cancer, making the EGFR an important target for therapy. EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition has not been effective in treating this tumor. Here we propose that primary resistance to EGFR inhibition in glioma cells results from a rapid compensatory response to EGFR inhibition that mediates cell survival. We show that in glioma cells expressing either EGFR wild-type or the mutant EGFRvIII, EGFR inhibition triggers a rapid adaptive response driven by increased tumor necrosis factor (TNF) secretion, which leads to activation in turn of c-Jun N-terminal kinase (JNK), the Axl receptor tyrosine kinase and extracellular signal-regulated kinases (ERK). Inhibition of this adaptive axis at multiple nodes rendered glioma cells with primary resistance sensitive to EGFR inhibition. Our findings provide a possible explanation for the failures of anti-EGFR therapy in GBM and suggest a new approach to the treatment of EGFR-expressing GBM using a combination of EGFR and TNF inhibition.

October 9, 2017

The large red blob (left) indicates an increase in the timing, or synchronization, between brain waves measured over the medial frontal cortex and right lateral prefrontal cortex. This enhanced timing across brain regions specifically …more

Two brain regions—the medial frontal and lateral prefrontal cortices—control most executive function. Robert Reinhart used high-definition transcranial alternating current stimulation (HD-tACS) to synchronize oscillations between them, improving brain processing. De-synchronizing did the opposite.

“If you make an error, this brain area fires,” says Reinhart, an assistant professor of psychological and brain sciences at Boston University. “If I tell you that you make an error, it also fires. If something surprises you, it fires.” Hit a sour note on the piano and the medial frontal cortex lights up, helping you correct your mistake as fast as possible. In healthy people, this region of the brain works hand in hand (or perhaps lobe in lobe) with a nearby region, the lateral prefrontal cortex, an area that stores rules and goals and also plays an important role in changing our decisions and actions.

“These are maybe the two most fundamental brain areas involved with executive function and self-control,” says Reinhart, who used a new technique called high-definition transcranial alternating current stimulation (HD-tACS) to stimulate these two regions with electrodes placed on a participant’s scalp. Using this new technology, he found that improving the synchronization of brain waves, or oscillations, between these two regions enhanced their communication with each other, allowing participants to perform better on laboratory tasks related to learning and self-control. Conversely, de-synchronizing or disrupting the timing of the brain waves in these regions impaired participants’ ability to learn and control their behavior, an effect that Reinhart could quickly fix by changing how he delivered the electrical stimulation. The work, published October 9, 2017, in the journalProceedings of the National Academy of Sciences (PNAS), suggests that electrical stimulation can quickly—and reversibly—increase or decrease executive function in healthy people and change their behavior. These findings may someday lead to tools that can enhance normal brain function, possibly helping treat disorders from anxiety to autism.

“We’re always looking for a link between brain activity and behavior—it’s not enough to have just one of those things. That’s part of what makes this finding so exciting,” says David Somers, a BU professor of psychological and brain sciences, who was not involved with the study. Somers likens the stimulation to a “turbo charge” for your brain. “It’s really easy to mess things up in the brain but much harder to actually improve function.”

Research has recently suggested that populations of millions of cells in the medial frontal cortex and the lateral prefrontal cortex may communicate with each other through the precise timing of their synchronized oscillations, and these brain rhythms appear to occur at a relatively low frequency (about four to eight cycles per second). While scientists have studied these waves before, Reinhart is the first to use HD-tACS to test how these populations of cells interact and whether their interactions are behaviorally useful for learning and decision-making. In his work, funded by the National Institutes of Health, Reinhart is able to use HD-tACS to isolate and alter these two specific brain regions, while also recording participants’ electrical brain activity via electroencephalogram (EEG).

“The science is much stronger, much more precise than what’s been done earlier,” says Somers.

In his first round of studies, Reinhart tested 30 healthy participants. Each subject wore a soft cap fitted with electrodes that stimulated brain activity, while additional electrodes monitored brain waves. (The procedure is safe, noninvasive, and doesn’t hurt, says Reinhart. “There’s a slight tingling for the first 30 seconds,” he says, “and then people habituate to it.”) Then, for 40 minutes, participants performed a time-estimation learning task, pressing a button when they thought 1.7 seconds had passed. Each time, the computer gave them feedback: too fast, too slow, or just right.

Reinhart tested each of the 30 participants three times, once up-regulating the oscillations, once disrupting them, and once doing nothing. In tests where Reinhart cranked up the synchrony between the two brain regions, people learned faster, made fewer errors, and—when they did make an error—adjusted their performance more accurately. And, when he instead disrupted the oscillations and decreased the synchrony—in a very rough sense, flicking the switch from “smart” to “dumb”—subjects made more errors and learned slower. The effects were so subtle that the people themselves did not notice any improvement or impairment in the task, but the results were statistically significant.

By precisely stimulating two brain areas to increase (or decrease) communications between them, Robert Reinhart, BU assistant professor of psychological and brain sciences, was able to increase (or decrease) participants’ learning ability …more

Reinhart then replicated the experiment in 30 new participants, adding another study parameter by looking at only one side of the brain at a time. In all cases, he found that the right hemisphere of the brain was more relevant to changing behavior.

Then came the most intriguing part of the study. Thirty more participants came in and tried the task. First, Reinhart temporarily disrupted each subject’s brain activity, watching as their brain waves de-synchronized and their performance on the task declined. But this time, in the middle of the task, Reinhart switched the timing of the stimulation—again, turning the knob from “dumb” to “smart.” Participants recovered their original levels of brain synchrony and learning behavior within minutes.

“We were shocked by the results and how quickly the effects of the stimulation could be reversed,” says Reinhart.

Though Reinhart cautions that these results are very preliminary, he notes that many psychiatric and neurological disorders—including anxiety, Parkinson’s, autism, schizophrenia, ADHD, and Alzheimer’s—demonstrate disrupted oscillations. Currently, most of these disorders are treated with drugs that act on receptors throughout the brain. “Drugs are really messy,” says Reinhart. “They often affect very large regions of brain.” He imagines, instead, a future with precisely targeted brain stimulation that acts only on one critical node of a brain network, “like a finer scalpel.” Reinhart’s next line of research will test the technology on people with anxiety disorders.

There is also, of course, the promise of what the technology might offer to healthy brains. Several companies already market brain stimulation devices that claim to both enhance learning and decrease anxiety. YouTube videos show how to make your own, with double-A batteries and off-the-shelf electronics, a practice Reinhart discourages. “You can hurt yourself,” he says. “You can get burned and have current ringing around your head for days.”

He does, however, see the appeal. “I had volunteers in previous research who came back and said, ‘Hey, where can I get one of these? I’d love to have it prior to an exam,'” he says. “That was after we debriefed them and they were reading the papers about it.”

Somers notes that there are still many questions to answer about the technology before it goes mainstream: How long can the effect last? How big can you make it? Can you generalize from a simple laboratory task too much more complicated endeavors? “But the biggest question,” says Somers, “is how far you can go with this technology.”

“Think about any given workday,” says Somers. “You need to be really ‘on’ for one meeting, so you set aside some time on your lunch break for some brain stimulation. I think a lot of people would be really into that—it would be like three cups of coffee without the jitters.”